CN114364665A - 调节白介素的前药 - Google Patents
调节白介素的前药 Download PDFInfo
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- CN114364665A CN114364665A CN202080063583.6A CN202080063583A CN114364665A CN 114364665 A CN114364665 A CN 114364665A CN 202080063583 A CN202080063583 A CN 202080063583A CN 114364665 A CN114364665 A CN 114364665A
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Abstract
Description
相关申请的交叉引用
本申请要求2019年7月16日提交的美国临时申请号62/874531的权益,将其公开内容通过引用以其整体并入本文。
技术领域
本发明涉及可用作通过作用于Tyk-2以引起信号转导抑制来调节IL-12、IL-23和/或IFNa的前药的化合物。本文提供了酰胺取代的杂环化合物的前药、包含此类化合物的组合物、以及它们的使用方法。本发明进一步涉及含有至少一种根据本发明的化合物的药物组合物,所述药物组合物可用于治疗哺乳动物的与IL-12、IL-23和/或IFNa的调节相关的病症。
背景技术
共有共同的p40亚基的异二聚体细胞因子白介素(IL)-12和IL-23由激活的抗原呈递细胞产生,并且在Th1和Th17细胞(在自身免疫中起着关键作用的两个效应T细胞谱系)的分化和增殖中至关重要。IL-23由p40亚基以及独特的p19亚基构成。IL-23通过由IL-23R和IL-12Rβ1构成的异二聚体受体起作用,是产生促炎细胞因子诸如IL-17A、IL-17F、IL-6和TNF-a的Th17细胞的存活和扩增必需的(McGeachy,M.J.等人,“The link between IL-23and Th17 cell-mediated immune pathologies”,Semin.Immunol.,19:372-376(2007))。这些细胞因子在介导许多自身免疫性疾病的病理生物学中至关重要,所述自身免疫性疾病包括类风湿性关节炎、多发性硬化、炎性肠病和狼疮。IL-12除了与IL-23共有的p40亚基外,还含有p35亚基并且通过由IL-12Rβ1和IL-12Rβ2构成的异二聚体受体起作用。IL-12是Th1细胞发育和IFNγ分泌必需的,IFNγ是通过刺激MHC的表达、将B细胞类别转换为IgG亚类以及激活巨噬细胞而在免疫中发挥决定性作用的细胞因子(Gracie,J.A.等人,“Interleukin-12induces interferon-gamma-dependent switching of IgGalloantibody subclass”,Eur.J.Immunol.,26:1217-1221(1996);Schroder,K.等人,“Interferon-gamma:an overview of signals,mechanisms and functions”,J.Leukoc.Biol.,75(2):163-189(2004))。
含有p40的细胞因子在自身免疫中的重要性通过如下发现证明:缺乏p40、p19或IL-23R的小鼠被保护免受尤其多发性硬化、类风湿性关节炎、炎性肠病、狼疮和银屑病等模式的疾病的影响(Kyttaris,V.C.等人,“Cutting edge:IL-23receptor deficiencyprevents the development of lupus nephritis in C57BL/6-lpr/lpr mice”,J.Immunol.,184:4605-4609(2010);Hong,K.等人,“IL-12,independently of IFN-gamma,plays a crucial role in the pathogenesis of a murine psoriasis like skindisorder”,J.Immunol.,162:7480-7491(1999);Hue,S.等人,“Interleukin-23drivesinnate and T cell-mediated intestinal inflammation”,J.Exp.Med.,203:2473-2483(2006);Cua,D.J.等人,“Interleukin-23rather than interleukin-12is the criticalcytokine for autoimmune inflammation of the brain”,Nature,421:744-748(2003);Murphy,C.A.等人,“Divergent pro-and anti-inflammatory roles for IL-23and IL-12in joint autoimmune inflammation”,J.Exp.Med.,198:1951-1957(2003))。
在人类疾病中,已经在银屑病病变中测量到p40和p19的高表达,并且已经在MS患者脑部中的活动性病变中和在活动性克罗恩病患者的肠粘膜中鉴定出Th17细胞(Lee,E.等人,“Increased expression of interleukin 23p19 and p40 in lesional skin ofpatients with psoriasis vulgaris”,J.Exp.Med.,199:125-130(2004);Tzartos,J.S.等人,“Interleukin-17production in central nervous system infiltrating T cellsand glial cells is associated with active disease in multiple sclerosis”,Am.J.Pathol.,172:146-155(2008))。活动性SLE患者中p19、p40和p35的mRNA水平也显示与非活动性SLE患者中的那些相比显著更高(Huang,X.等人,“Dysregulated expression ofinterleukin-23and interleukin-12subunits in systemic lupus erythematosuspatients”,Mod.Rheumatol.,17:220-223(2007)),并且来自狼疮患者的T细胞具有占主导地位的Th1表型(Tucci,M.等人,“Overexpression of interleukin-12and T helper1predominance in lupus nephritis”,Clin.Exp.Immunol.,154:247-254(2008))。
此外,全基因组关联研究已经鉴定出了许多与慢性炎性和自身免疫性疾病相关的基因座,这些基因座编码在IL-23和IL-12途径中起作用的因子。这些基因包括IL23A、IL12A、IL12B、IL12RB1、IL12RB2、IL23R、JAK2、TYK2、STAT3和STAT4(Lees,C.W.等人,“NewIBD genetics:common pathways with other diseases”,Gut,60:1739-1753(2011);Tao,J.H.等人,“Meta-analysis of TYK2 gene polymorphisms association withsusceptibility to autoimmune and inflammatory diseases”,Mol.Biol.Rep.,38:4663-4672(2011);Cho,J.H.等人,“Recent insights into the genetics ofinflammatory bowel disease”,Gastroenterology,140:1704-1712(2011))。
事实上,抗p40治疗(抑制IL-12和IL-23两者)和IL-23特异性抗p19疗法已显示在包括银屑病、克罗恩病和银屑病性关节炎在内的疾病中的自身免疫的治疗中是有效的(Leonardi,C.L.等人,"PHOENIX 1study investigators.Efficacy and safety ofustekinumab,a human interleukin-12/23monoclonal antibody,in patients withpsoriasis:76-week results from a randomized,double-blind,placebo-controlledtrial(PHOENIX 1)",Lancet,371:1665-1674(2008);Sandborn,W.J.等人,"UstekinumabCrohn's Disease Study Group.A randomized trial of Ustekinumab,a humaninterleukin-12/23monoclonal antibody,in patients with moderate-to-severeCrohn's disease",Gastroenterology,135:1130-1141(2008);Gottlieb,A.等人,"Ustekinumab,a human interleukin 12/23monoclonal antibody,for psoriaticarthritis:randomized,double-blind,placebo-controlled,crossover trial",Lancet,373:633-640(2009))。因此,可以预期,抑制IL-12和IL-23作用的药剂在人自身免疫性障碍中具有治疗益处。
包括IFNa成员以及IFNP、IFNe、IFNK和IFNω的I型干扰素(IFN)组通过异二聚体IFNa/β受体(IFNAR)起作用。I型IFN在先天免疫系统和适应性免疫系统中均具有多种效应,包括激活细胞和体液免疫应答以及增强自身抗原的表达和释放(Hall,J.C.等人,“Type Iinterferons:crucial participants in disease amplification in autoimmunity”,Nat.Rev.Rheumatol.,6:40-49(2010))。
在患有系统性红斑狼疮(SLE,一种具有潜在致命性的自身免疫性疾病)的患者中,干扰素(IFN)a(I型干扰素)血清水平增加或I型IFN调节的基因(所谓的IFNa签名)在外周血单核细胞和受影响器官中的表达增加已经在大多数患者中得到证明(Bennett,L.等人,“nterferon and granulopoiesis signatures in systemic lupus erythematosusblood”J.Exp.Med.,197:711-723(2003);Peterson,K.S等人,“Characterization ofheterogeneity in the molecular pathogenesis of lupus nephritis fromtranscriptional profiles of laser-captured glomeruli”,J.Clin.Invest.,113:1722-1733(2004)),并且一些研究显示,血清IFNa水平与疾病活动度和严重程度相关(Bengtsson,A.A.等人,“Activation of type I interferon system in systemic lupuserythematosus correlates with disease activity but not with antiretroviralantibodies”,Lupus,9:664-671(2000))。IFNa在狼疮病理生物学中的直接作用通过以下观察而得到证明:向患有恶性或病毒性疾病的患者施用IFNa可以诱导狼疮样综合征。此外,狼疮易感小鼠中IFNAR的缺失提供了对自身免疫、疾病严重程度和致死性的高度保护(Santiago-Raber,M.L.等人,“Type-I interferon receptor deficiency reduceslupus-like disease in NZB mice”,J.Exp.Med.,197:777-788(2003)),并且全基因组关联研究已经鉴定出与狼疮相关的基因座,这些基因座编码在I型干扰素通路中起作用的因子,包括IRF5、IKBKE、TYK2和STAT4(Deng,Y.等人,“Genetic susceptibility to systemiclupus erythematosus in the genomic era”,Nat.Rev.Rheumatol.,6:683-692(2010);Sandling,J.K.等人,“A candidate gene study of the type I interferon pathwayimplicates IKBKE and IL8 as risk loci for SLE”,Eur.J.Hum.Genet.,19:479-484(2011))。除了狼疮之外,有证据表明I型干扰素介导的途径的异常激活在其他自身免疫性疾病(诸如肖格伦综合征和硬皮病)的病理生物学中是十分重要的(U.等人,“Activation of the type I interferon system in primarysyndrome:apossible etiopathogenic mechanism”,Arthritis Rheum.,52:1185-1195(2005);Kim,D.等人,“Induction of interferon-alpha by scleroderma sera containingautoantibodies to topoisomerase I:association of higher interferon-alphaactivity with lung fibrosis”,Arthritis Rheum.,58:2163-2173(2008))。因此,可以预期抑制I型干扰素反应的作用的药剂在人类自身免疫性疾病中具有治疗益处。
酪氨酸激酶2(Tyk2)是非受体酪氨酸激酶的Janus激酶(JAK)家族的成员,并且已显示在小鼠(Ishizaki,M.等人.,“Involvement of Tyrosine Kinase-2in Both the IL-12/Th1 and IL-23/Th17 Axes In vivo”,J.Immunol.,187:181-189(2011);Prchal-Murphy,M.等人,“TYK2kinase activity is required for functional type Iinterferon responses in vivo”,PLoS One,7:e39141(2012))和人类(Minegishi,Y.等人,“Human tyrosine kinase 2deficiency reveals its requisite roles in multiplecytokine signals involved in innate and acquired immunity”,Immunity,25:745-755(2006))两者中调节IL-12、IL-23和I型干扰素的受体下游的信号转导级联中至关重要。Tyk2介导转录因子STAT家族成员的受体诱导磷酸化,这是导致STAT蛋白二聚化和STAT依赖性促炎基因转录的重要信号。Tyk2缺乏小鼠对结肠炎、银屑病和多发性硬化的实验模型具有抗性,证明了Tyk2介导的信号传导在自身免疫和相关障碍中的重要性(Ishizaki,M.等人,“Involvement of Tyrosine Kinase-2in Both the IL-12/Th1 and IL-23/Th17 AxesIn vivo”J.Immunol.,187:181-189(2011);Oyamada,A.等人,“Tyrosine kinase 2playscritical roles in the pathogenic CD4 T cell responses for the development ofexperimental autoimmune encephalomyelitis”J.Immunol.,183:7539-7546(2009))。
在人类中,表达Tyk2的非活性变体的个体受到保护免患多发性硬化和可能的其他自身免疫性障碍(Couturier,N.等人,“Tyrosine kinase 2variant influences Tlymphocyte polarization and multiple sclerosis susceptibility”,Brain,134:693-703(2011))。全基因组关联研究显示,Tyk2的其他变体与自身免疫性障碍诸如克罗恩病、银屑病、系统性红斑狼疮和类风湿性关节炎相关,进一步证明了Tyk2在自身免疫中的重要性(Ellinghaus,D.等人,“Combined Analysis of Genome-wide Association Studies forCrohn Disease and Psoriasis Identifies Seven Shared Susceptibility Loci”Am.J.Hum.Genet.,90:636-647(2012);Graham,D.等人,“Association of polymorphismsacross the tyrosine kinase gene,TYK2 in UK SLE families”,Rheumatology(Oxford),46:927-930(2007);Eyre,S.等人,“High-density genetic mappingidentifies new susceptibility loci for rheumatoid arthritis”,Nat.Genet.,44:1336-1340(2012))。
鉴于可能通过涉及细胞因子和/或干扰素调节的治疗而受益的病症,能够调节细胞因子和/或干扰素(诸如IL-12、IL-23和/或IFNa)的新化合物以及使用这些化合物的方法可能为有此需要的各种各样的患者提供实质性的治疗益处。
美国专利号9,663,467公开了可用于治疗与IL-12、IL-23和/或IFNa的调节相关的疾病和病症诸如自身免疫性疾病和炎性疾病的化合物。此参考文献已转让给本发明的受让人,并通过引用以其整体并入本文。
其中公开的以下所示的化合物
已显示出针对靶标的活性。
美国专利号9,505,748还公开了可用于治疗与IL-12、IL-23和/或IFNa的调节相关的疾病和病症诸如自身免疫性疾病和炎性疾病的化合物。此参考文献已转让给本发明的受让人,并通过引用以其整体并入本文。
其中公开的以下所示的化合物
已显示出针对靶标的活性。
如可以理解,仍然需要改善以上化合物向患者的递送。
申请人已经发现化合物(I)和(II)的前药,其分别可用于化合物(I)和(II)的施用。与化合物(I)和(II)相比,所述前药在生理重要的pH值下具有更好的溶解度,并且令人惊讶地允许化合物(I)和(II)以更宽的剂量范围和/或更宽的药物配制品范围施用。提供的这些前药化合物可用作药物,所述药物具有希望的稳定性、生物利用度、治疗指数和对其可药用性重要的毒性值。
发明内容
本发明涉及化合物(I)和(II)的前药,其可通过抑制Tyk2介导的信号转导而用作IL-12、IL-23和/或IFNa的调节剂。
本发明还提供了用于制备本发明化合物的方法和中间体。
本发明还提供了药物组合物,其包含药学上可接受的载体和至少一种本发明化合物。
本发明还提供了一种用于通过抑制Tyk-2介导的信号转导来调节IL-12、IL-23和/或IFNa的方法,其包括向需要这种治疗的宿主施用治疗有效量的至少一种本发明化合物。
本发明还提供了一种用于治疗增殖性、代谢性、过敏性、自身免疫性和炎性疾病的方法,其包括向需要这种治疗的宿主施用治疗有效量的至少一种本发明化合物。
优选的实施方案是一种用于治疗炎性和自身免疫性疾病或障碍的方法。出于本发明的目的,炎性和自身免疫性疾病或障碍包括具有炎性或自身免疫性组分的任何疾病。
一个替代性优选实施方案是治疗代谢性疾病(包括2型糖尿病和动脉粥样硬化)的方法。
本发明还提供了本发明的化合物在制造用于治疗癌症的药剂中的用途。
本发明还提供了用于疗法的本发明化合物。
本发明的这些和其他特征将随本公开文本的继续以扩展的形式加以阐述。
附图说明
通过参照以下所描述的附图来说明本发明。
图1示出了化合物I的前药的PK。使用以下符号的以下剂量向大鼠口服给药:(◇)-5mpk、(D)-25mpk和(◇)-150mpk。观察到的最大循环前药是母体的<0.05%(150mpk剂量)。
具体实施方式
本发明的第一方面提供了如下所示的化合物(I)和(II)的前药
在本发明的第二方面,提供了以下本发明化合物:
或其盐。
在本发明的第三方面,提供了如下所示的化合物(I)的前药
或其盐。
在本发明的第四方面,提供了如下所示的化合物(II)的前药
或其盐。
在另一方面,本发明提供了一种选自第一方面的范围内的示例性例子的化合物,或其药学上可接受的盐或立体异构体。
在另一方面,本发明提供了一种选自任何上述方面的范围内的化合物的任何子集列表的化合物。
在另一个实施方案中,提供了一种药物组合物,其包含一种或多种式I的化合物和药学上可接受的载体或稀释剂。
本发明还涉及可用于通过作用于Tyk-2引起信号转导抑制来治疗与IL-12、IL-23和/或IFNa的调节相关的疾病的药物组合物,其包含式I的化合物或其药学上可接受的盐,以及药学上可接受的载体或稀释剂。
本发明进一步涉及治疗与IL-12、IL-23和/或IFNa的调节相关的疾病的方法,其包括向需要这种治疗的患者施用治疗有效量的根据式I的化合物。
本发明还提供了用于制备本发明化合物的方法和中间体。
本发明还提供了一种用于治疗增殖性、代谢性、过敏性、自身免疫性和炎性疾病的方法(或本发明的化合物用于制造用于治疗这些疾病的药剂的用途),包括向需要这种治疗的宿主施用治疗有效量的至少一种本发明的化合物。
本发明还提供了一种治疗炎性疾病或自身免疫性疾病的方法(或本发明的化合物用于制造治疗这些疾病的药剂的用途),其包括向需要这种治疗的患者施用治疗有效量的式I的化合物。
本发明还提供了一种用于治疗疾病的方法(或本发明的化合物用于制造用于治疗这些疾病的药剂的用途),包括向需要这种治疗的患者施用治疗有效量的式I的化合物,其中所述疾病是类风湿性关节炎、多发性硬化、系统性红斑狼疮(SLE)、狼疮性肾炎、皮肤狼疮、炎性肠病、银屑病、克罗恩病、银屑病性关节炎、肖格伦综合征、系统性硬皮病、溃疡性结肠炎、格雷夫斯病、盘状红斑狼疮、成人发作的斯蒂尔病、全身性发作的幼年特发性关节炎、痛风、痛风性关节炎、1型糖尿病、胰岛素依赖型糖尿病、败血症、感染性休克、志贺氏菌病、胰腺炎(急性或慢性)、肾小球肾炎、自身免疫性胃炎、糖尿病、自身免疫性溶血性贫血、自身免疫性中性粒细胞减少症、血小板减少症、特应性皮炎、重症肌无力、胰腺炎(急性或慢性)、强直性脊柱炎、寻常型天疱疮、古德帕斯彻病、抗磷脂综合征、特发性血小板减少症、ANCA相关血管炎、天疱疮、川崎病、慢性炎性脱髓鞘性多发性神经病(CIDP)、皮肌炎、多肌炎、葡萄膜炎、格-巴二氏综合征、自身免疫性肺炎症、自身免疫甲状腺炎、自身免疫性炎性眼病、和慢性脱髓鞘性多发性神经病。
本发明还提供了一种治疗炎性疾病或自身免疫性疾病的方法(或本发明的化合物用于制造用于治疗所述疾病的药剂的用途),包括向需要这种治疗的患者施用治疗有效量的式I的化合物,其中所述疾病选自系统性红斑狼疮(SLE)、狼疮性肾炎、皮肤狼疮、克罗恩病、溃疡性结肠炎、1型糖尿病、银屑病、类风湿性关节炎、全身性发作的幼年特发性关节炎、强直性脊柱炎、和多发性硬化。
本发明还提供了一种用于治疗类风湿性关节炎的方法(或本发明的化合物用于制造用于治疗类风湿性关节炎的药剂的用途),其包括向需要这种治疗的患者施用治疗有效量的式I的化合物。
此外,本发明还提供了一种治疗病症的方法(或本发明的化合物用于制造用于治疗这些病症的药剂的用途),包括向需要这种治疗的患者施用治疗有效量的式I的化合物,其中所述病症选自急性骨髓性白血病、慢性骨髓性白血病、转移性黑色素瘤、卡波西肉瘤、多发性骨髓瘤、实体瘤、眼部新生血管、和婴儿血管瘤、B细胞淋巴瘤、系统性红斑狼疮(SLE)、类风湿性关节炎、银屑病性关节炎、多发性血管炎、特发性血小板减少性紫癜(ITP)、重症肌无力、过敏性鼻炎、多发性硬化(MS)、移植排斥、I型糖尿病、膜性肾炎、炎性肠病、自身免疫性溶血性贫血、自身免疫性甲状腺炎、冷和热凝集素疾病、伊文思综合征、溶血性尿毒症综合征/血栓性血小板减少性紫癜(HUS/TTP)、结节病、肖格伦综合征、周围神经病变、寻常型天疱疮和哮喘。
本发明还提供了一种治疗IL-12、IL-23和/或IFNa介导的疾病的方法(或本发明的化合物用于制造用于治疗这些疾病的药剂的用途),其包括向需要这种治疗的患者施用治疗有效量的式I的化合物。
本发明还提供了一种治疗IL-12、IL-23和/或IFNa介导的疾病的方法(或本发明的化合物用于制造用于治疗这些疾病的药剂的用途),其包括向需要这种治疗的患者施用治疗有效量的式I的化合物,其中所述IL-12、IL-23和/或IFNa介导的疾病是通过IL-12、IL-23和/或IFNa调节的疾病。
本发明还提供了一种治疗疾病的方法,其包括向需要这种治疗的患者施用与其他治疗剂组合的治疗有效量的式I的化合物。
本发明还提供了用于疗法的本发明化合物。
在另一个实施方案中,式I的化合物选自例示的化合物或例示的化合物的组合或者本文其他实施方案。
在另一个实施方案中,提供了在至少一种下述测定中IC50<1000nM的化合物。
本发明可以在不背离其精神或基本属性的情况下以其他特定形式实施。本发明涵盖本文所指出的本发明优选方面和/或实施方案的所有组合。应理解,可以将本发明的任何和所有实施方案与任何其他一个或多个实施方案结合来描述另外的更优选的实施方案。还应理解,优选实施方案的每个单独要素是其自己独立的优选实施方案。此外,实施方案的任何要素意在与来自任何实施方案的任何和所有其他要素组合来描述另外的实施方案。
发明详述
以下是本说明书和所附权利要求中使用的术语的定义。除非另有指示,否则本文提供的对于基团或术语的初始定义适用于整个说明书和权利要求书中的该基团或术语(单独地或作为另一基团的一部分)。
本发明的化合物可以具有一个或多个不对称中心。除非另外指示,否则本发明化合物的所有手性(对映异构体和非对映异构体)和外消旋形式均包括在本发明中。烯烃、C=N双键等的许多几何异构体也可以存在于所述化合物中,并且所有此类稳定异构体均考虑在本发明中。描述了本发明的化合物的顺式和反式几何异构体,并且其可以作为异构体的混合物或作为分开的异构形式分离。本发明化合物可以以光学活性或外消旋形式分离。本领域熟知如何制备光学活性形式,诸如通过拆分外消旋形式或通过从光学活性起始材料合成。除非特别指出具体的立体化学或异构体形式,否则意指结构的所有手性(对映异构和非对映异构)和外消旋形式以及所有几何异构形式。
当任何变量(例如,R3)在化合物的任何成分或式中出现多于一次时,其在每次出现时的定义独立于其在其他每次出现时的定义。因此,例如,如果显示基团被0-2个R3取代,则所述基团可以任选地被最多两个R3基团取代,并且R3在每次出现时独立地选自R3的定义。另外,只有当取代基和/或变量的组合产生稳定的化合物时,此类组合才是允许的。
当显示与取代基的键与连接环中两个原子的键交叉时,则此类取代基可键合至所述环上的任何原子。当列出取代基而没有指示这个取代基是经由哪个原子键合至给定式的化合物的其余部分时,则这个取代基可以经由此类取代基中的任何原子键合。只有当取代基和/或变量的组合产生稳定的化合物时,此类组合才可被允许。
在本发明的化合物上存在氮原子(例如,胺)的情况下,可以通过用氧化剂(例如,MCPBA和/或过氧化氢)处理将这些氮原子转化为N-氧化物,以得到本发明的其他化合物。因此,所有显示和要求保护的氮原子被认为包括所示的氮及其N-氧化物(N→O)衍生物两者。
不在两个字母或符号之间的短划线“-”用于指示取代基的附接点。例如,-CONH2通过碳原子附接。
式I的化合物可以游离形式(没有电离)存在或可以形成盐,所述盐也在本发明的范围内。除非另有指定,否则提及本发明的化合物应理解为包括提及游离形式及其盐。术语“一种或多种盐”表示与无机和/或有机酸和碱形成的酸式和/或碱式盐。此外,术语“一种或多种盐”可以包括两性离子(内盐),例如当式I的化合物含有碱性部分(诸如胺或吡啶或咪唑环)和酸性部分(诸如羧酸)时。药学上可接受的(即,无毒的生理学上可接受的)盐是优选的,如例如其中阳离子对盐的毒性或生物活性没有显著贡献的可接受的金属盐和胺盐。然而,其他盐可以例如用于可在制备期间采用的分离或纯化步骤中,并且因此涵盖在本发明的范围内。式I的化合物的盐可以例如通过使式I的化合物与一定量的酸或碱(诸如当量)在介质(诸如盐在其中沉淀的介质)中或在水性介质中反应,随后冻干而形成。
示例性酸加成盐包括乙酸盐(诸如与乙酸或三卤乙酸(例如三氟乙酸)形成的那些)、己二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐(与盐酸形成)、氢溴酸盐(与溴化氢形成)、氢碘化物、2-羟基乙磺酸盐、乳酸盐、马来酸盐(与马来酸形成)、甲磺酸盐(与甲磺酸形成)、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、水杨酸盐、琥珀酸盐、硫酸盐(诸如与硫酸形成的那些)、磺酸盐(诸如本文中提到的那些)、酒石酸盐、硫氰酸盐、甲苯磺酸盐(toluenesulfonate)(诸如甲苯磺酸盐(tosylate))、十一烷酸盐等。
示例性碱式盐包括铵盐;碱金属盐,诸如钠盐、锂盐和钾盐;碱土金属盐,诸如钙盐和镁盐;钡盐、锌盐和铝盐;与有机碱(例如有机胺)的盐,所述有机碱如三烷胺(诸如三乙胺)、普鲁卡因、二苄胺、N-苄基-β-苯乙胺、1-二苯羟甲胺(ephenamine)、N,N'-二苄乙烯-二胺、脱氢枞胺、N-乙基哌啶、苄胺、二环己胺或类似的药学上可接受的胺;以及与氨基酸(诸如精氨酸、赖氨酸等)的盐。碱性含氮基团可以用以下试剂季铵化:如低级烷基卤化物(例如,甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物)、二烷基硫酸盐(例如,二甲基、二乙基、二丁基和二戊基的硫酸盐)、长链卤化物(例如,癸基、月桂基、肉豆蔻基和硬脂酰基的氯化物、溴化物和碘化物)、芳烷基卤化物(例如,苄基和苯乙基的溴化物)以及其他试剂。优选的盐包括单盐酸盐、硫酸氢盐、甲磺酸盐、磷酸盐或硝酸盐。
本文采用短语“药学上可接受的”指代在合理医学判断范围内适合于与人和动物组织接触使用而没有过多的毒性、刺激、过敏反应或其他问题或并发症,与合理的效益/风险比相称的那些化合物、材料、组合物和/或剂型。
如本文所用,“药学上可接受的盐”是指所公开化合物的衍生物,其中母体化合物通过制造其酸盐或碱盐而被修饰。药学上可接受的盐的例子包括但不限于诸如胺的碱性基团的矿物酸盐或有机酸盐;和诸如羧酸的酸性基团的碱性盐或有机盐。药学上可接受的盐包括常规无毒盐或例如从无毒无机酸或有机酸形成的母体化合物的季铵盐。例如,此类常规无毒盐包括从如下无机酸衍生的那些:例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸和硝酸;以及由如下有机酸制备的盐:例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、双羟萘酸(pamoic)、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、磺胺酸、2-乙酰氧基苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、和羟乙磺酸等。
本发明的药学上可接受的盐可以通过常规的化学方法由含有碱性或酸性部分的母体化合物合成。通常,此类盐可以通过使这些化合物的游离酸或碱形式与化学计算量的适当的碱或酸在水中或在有机溶剂中或者在这两者的混合物中反应来制备;通常,非水性介质如醚、乙酸乙酯、乙醇、异丙醇或乙腈是优选的。合适的盐的列表发现于Remington'sPharmaceutical Sciences,第18版,Mack Publishing Company,Easton,PA(1990),将其公开内容通过引用特此并入。
如果可适用,则考虑本发明化合物的所有立体异构体,呈混合物或呈纯的或基本上纯的形式。立体异构体可以包括通过具有一个或多个手性原子而为光学异构体的化合物,以及借助于围绕一个或多个键有限旋转而为光学异构体(阻转异构体)的化合物。根据本发明的化合物的定义涵盖所有可能的立体异构体及其混合物。其非常特定地涵盖外消旋形式和具有指定活性的经分离光学异构体。外消旋形式可以通过物理方法拆分,所述物理方法例如像非对映异构体衍生物的分级结晶、分离或结晶或者通过手性柱色谱法分离。可以从常规方法的外消旋体中获得单独的光学异构体,所述常规方法例如像用光学活性酸形成盐,然后结晶。
本发明旨在包括存在于本发明化合物中的原子的所有同位素。同位素包括原子数相同但质量数不同的那些原子。作为一般例子而非限制,氢的同位素包括氘和氚。碳的同位素包括13C和14C。本发明的同位素标记的化合物通常可以通过本领域技术人员已知的常规技术或通过与本文所述的那些类似的方法,使用适当的同位素标记的试剂代替以其他方式使用的未标记的试剂来制备。
式I的化合物及其盐可以其互变异构形式存在,其中氢原子转置到分子的其他部分,并且因此分子的原子之间的化学键得以重排。应当理解,所有互变异构形式,只要它们可能存在,都包括在本发明内。另外,本发明化合物可以具有反式和顺式异构体。
还应当理解,式I的化合物的溶剂化物(例如,水合物)也在本发明的范围内。溶剂化方法在本领域中是通常已知的。
效用
本发明化合物调节IL-23刺激的和IFNa刺激的细胞功能,包括基因转录。可由本发明化合物调节的其他类型的细胞功能包括但不限于IL-12刺激的反应。
因此,式I的化合物通过作用于Tyk2以介导信号转导而在治疗与IL-23或IFNa的功能的调节相关,并且特别是与IL-23、IL-12和/或IFNa的功能的选择性抑制相关的病症中具有效用。此类病症包括IL-23、IL-12或IFNa相关疾病,其中发病机制通过这些细胞因子介导。
如本文所用,术语“治疗”(“treating”或“treatment”)涵盖对哺乳动物、特别是人类中的疾病状态的治疗,并且包括:(a)预防或延迟哺乳动物中疾病状态的发生,特别是当这个哺乳动物易患所述疾病状态但尚未被诊断为患有所述疾病状态时;(b)抑制疾病状态,即,阻止其发展;和/或(c)实现症状或疾病状态的完全或部分减少和/或缓解、改善、减轻或治愈疾病或障碍和/或其症状。
鉴于它们作为IL-23、IL-12和IFNa刺激的细胞应答的调节剂的活性,式I的化合物可用于治疗IL-23、IL-12或IFNa相关疾病,所述疾病分别包括但不限于炎性疾病,诸如克罗恩病、溃疡性结肠炎、哮喘、移植物抗宿主病、同种异体移植物排斥、慢性阻塞性肺病;自身免疫性疾病,诸如格雷夫斯病、类风湿性关节炎、系统性狼疮红斑、皮肤狼疮、狼疮性肾炎、盘状红斑狼疮、银屑病;自身炎性疾病,包括CAPS、TRAPS、FMF、成人发作的斯蒂尔病、全身性发作的幼年特发性关节炎、痛风、痛风性关节炎;代谢性疾病,包括2型糖尿病、动脉粥样硬化、心肌梗塞;破坏性骨障碍,诸如骨吸收疾病、骨关节炎、骨质疏松症、多发性骨髓瘤相关骨障碍;增生性障碍,诸如急性骨髓性白血病、慢性骨髓性白血病;血管生成障碍,诸如包括实体瘤、眼部新生血管和婴儿血管瘤的血管生成障碍;感染性疾病,诸如败血症、感染性休克和志贺氏菌病;神经退行性疾病,诸如阿尔茨海默病、帕金森病、由创伤性损伤引起的脑缺血或神经退行性疾病,肿瘤和病毒性疾病,诸如转移性黑色素瘤、卡波西肉瘤、多发性骨髓瘤,以及HIV感染和CMV视网膜炎,AIDS。
更特别地,可用本发明的化合物治疗的特定病症或疾病包括但不限于胰腺炎(急性或慢性)、哮喘、过敏、成人呼吸窘迫综合征、慢性阻塞性肺病、肾小球肾炎、类风湿性关节炎、系统性红斑狼疮、皮肤狼疮、狼疮性肾炎、盘状红斑狼疮、硬皮病、慢性甲状腺炎、格雷夫斯病、自身免疫性胃炎、糖尿病、自身免疫性溶血性贫血、自身免疫性中性粒细胞减少症、血小板减少症、特应性皮炎、慢性活动性肝炎、重症肌无力、多发性硬化、炎性肠病、溃疡性结肠炎、克罗恩病、银屑病、移植物抗宿主病、内毒素引起的炎性反应、结核病、动脉粥样硬化、肌肉退化、恶病质、银屑病性关节炎、莱特尔综合征、痛风、创伤性关节炎、风疹关节炎、急性滑膜炎、胰腺β细胞病;以大量嗜中性粒细胞浸润为特征的疾病;类风湿性脊椎炎、痛风性关节炎和其他关节炎病症、脑型疟疾、慢性肺炎性疾病、矽肺病、肺结节病、骨吸收疾病、同种异体移植物排斥、感染引起的发热和肌痛、继发于感染的恶病质、瘢痕疙瘩形成、瘢痕组织形成、溃疡性结肠炎、热病、流感、骨质疏松症、骨关节炎、急性骨髓性白血病、慢性骨髓性白血病、转移性黑色素瘤、卡波西肉瘤、多发性骨髓瘤、败血症、感染性休克、和志贺氏菌病;阿尔茨海默病、帕金森病、创伤性损伤引起的脑缺血或神经退行性疾病;血管生成障碍,包括实体瘤、眼部新生血管和婴儿血管瘤;病毒性疾病,包括急性肝炎感染(包括甲型肝炎、乙型肝炎和丙型肝炎)、HIV感染和CMV视网膜炎、AIDS、ARC或恶性肿瘤和疱疹;中风、心肌缺血、中风心脏病发作中的缺血、器官缺氧[这应该是低氧症]、血管增生、心脏和肾脏再灌注损伤、血栓形成、心脏肥大、凝血酶诱导的血小板聚集、内毒素血症和/或中毒性休克综合征、与前列腺素内过氧化酶合酶-2相关的病症、和寻常型天疱疮。优选的治疗方法是其中病症选自克罗恩病、溃疡性结肠炎、同种异体移植物排斥、类风湿性关节炎、银屑病、强直性脊柱炎、银屑病性关节炎和寻常型天疱疮的那些。可替代地,优选治疗方法是其中病症选自缺血再灌注损伤的那些,所述缺血再灌注损伤包括由中风引起的脑缺血再灌注损伤和由心肌梗塞引起的心肌缺血再灌注损伤。另一种优选的治疗方法是其中病症是多发性骨髓瘤的方法。
当在本文使用术语“IL-23、IL-12和/或IFNa相关病症”或“IL-23、IL-12和/或IFNa相关疾病或障碍”时,所述术语各自旨在涵盖以上鉴定的所有病症,如同详细重复一般,以及受IL-23、IL-12和/或IFNa影响的任何其他病症。
因此,本发明提供了用于治疗此类病症的方法,其包括向有需要的受试者施用治疗有效量的至少一种式I的化合物或其盐。“治疗有效量”旨在包括本发明的化合物在单独或组合施用时有效抑制IL-23、IL-12和/或IFNa功能和/或治疗疾病的量。
治疗IL-23、IL-12和/或IFNa相关的病症的方法可以包括将式I的化合物单独或与彼此组合和/或与用于治疗此类病症的其他合适治疗剂组合地施用。因此,“治疗有效量”还旨在包括所要求保护的化合物的组合有效抑制IL-23、IL-12和/或IFNa功能和/或治疗与IL-23、IL-12和/或IFNa相关的疾病的量。
此类其他治疗剂的例子包括皮质类固醇、咯利普兰、卡弗他丁、细胞因子抑制性消炎药(CSAID)、白介素-10、糖皮质激素、水杨酸盐、一氧化氮和其他免疫抑制剂;核转位抑制剂,诸如脱氧精胍菌素(DSG);非类固醇消炎药(NSAID),诸如布洛芬、塞来昔布和罗非昔布;类固醇,诸如泼尼松或地塞米松;抗病毒剂,诸如阿巴卡韦;抗增殖剂,诸如甲氨蝶呤、来氟米特、FK506(他克莫司,);抗疟疾药,诸如羟氯喹;细胞毒性药物,诸如硫唑嘌呤和环磷酰胺;TNF-a抑制剂,诸如替尼达普、抗TNF抗体或可溶性TNF受体、和雷帕霉素(西罗莫司或)或其衍生物。
当与本发明的化合物组合使用时,以上其他治疗剂可以例如以Physicians’DeskReference(PDR)中指示的或者如本领域普通技术人员以其他方式确定的那些量来使用。在本发明的方法中,此类一种或多种其他治疗剂可以在施用本发明的化合物之前、同时或之后施用。本发明还提供能通过抑制Tyk2介导的信号转导来治疗IL-23、IL-12和/或IFNa相关病症的医药组合物,所述病症包括IL-23、IL-12和/或IFNa介导的疾病,如上所述。
本发明的组合物可以含有如上所描述的其他治疗剂,并且可以例如通过使用常规的固体或液体媒介物或稀释剂以及适合于所希望的施用方式的类型的药物添加剂(例如,赋形剂、粘合剂、防腐剂、稳定剂、调味剂等)根据技术(诸如药物配制领域熟知的那些)来配制。
因此,本发明进一步包括包含一种或多种式I的化合物和药学上可接受的载体的组合物。
“药学上可接受的载体”是指本领域通常接受的用于将生物活性剂递送至动物、特别是哺乳动物的介质。根据很好地在本领域普通技术人员的认知范围内的许多因素配制药学上可接受的载体。这些因素包括但不限于所配制的活性剂的类型和性质;有待被施用含有药剂的组合物的受试者;组合物的预期施用途径;以及所靶向的治疗适应症。药学上可接受的载体包括水性和非水性液体介质两者,以及多种固体和半固体剂型。此类载体可包括除活性剂之外的许多不同的成分和添加剂,此类另外的成分出于本领域普通技术人员熟知的多种原因(例如,稳定活性剂、粘合剂等)被包括在配制品中。合适的药学上可接受的载体及其选择中涉及的因素的描述在多种可容易获得的来源(例如像Remington'sPharmaceutical Sciences,第17版(1985))中找到,将其通过引用以其整体并入本文。
式I的化合物可以通过适合于待治疗病症的任何手段施用,这可取决于对位点特异性治疗的需要或待递送的药物的量。局部施用通常对于皮肤相关疾病是优选的,并且全身性治疗对于癌性或癌变前病症是优选的,但是也考虑其他递送模式。例如,化合物可以口服递送,诸如以片剂、胶囊、颗粒、粉末、或包括糖浆在内的液体配制品的形式;局部递送,诸如以溶液、悬浮液、凝胶或软膏的形式;舌下递送;经颊递送;肠胃外递送,诸如通过皮下、静脉内、肌肉内或胸骨内注射或输注技术(例如,作为无菌可注射水性或非水性的溶液或悬浮液);经鼻递送,诸如通过吸入喷雾;局部递送,诸如以乳膏或软膏的形式;直肠递送,诸如以栓剂的形式;或脂质体递送。可以施用含有无毒的药学上可接受的媒介物或稀释剂的剂量单位配制品。化合物可以适合于立即释放或延长释放的形式施用。立即释放或延长释放可以用合适的药物组合物来实现,或者,特别是在延长释放的情况下,用诸如皮下植入物或渗透泵的装置来实现。
用于口服施用的示例性组合物包括悬浮液,所述悬浮液可含有例如用于赋予体积的微晶纤维素、作为悬浮剂的海藻酸或海藻酸钠、作为粘度增强剂的甲基纤维素、以及甜味剂或调味剂,诸如本领域已知的那些;以及立即释放片剂,所述立即释放片剂可含有例如微晶纤维素、磷酸二钙、淀粉、硬脂酸镁和/或乳糖和/或其他赋形剂、粘合剂、增量剂、崩解剂、稀释剂和润滑剂,诸如本领域已知的那些。本发明的化合物还可以通过舌下和/或经颊施用来口服递送,例如采用模制、压缩或冷冻干燥的片剂。示例性组合物可以包含快速溶解的稀释剂,诸如甘露糖醇、乳糖、蔗糖和/或环糊精。此类配制品中还可以包含高分子量赋形剂,诸如纤维素或聚乙二醇(PEG);帮助粘膜粘附的赋形剂,诸如羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、羧甲基纤维素钠(SCMC)和/或马来酸酐共聚物(例如,);和控制释放的试剂,诸如聚丙烯酸共聚物(例如,CARBOPOL)。为便于制造和使用,还可以添加润滑剂、助流剂、调味剂、着色剂和稳定剂。
用于鼻用气雾剂或吸入施用的示例性组合物包括溶液,所述溶液可含有例如苯甲醇或其他合适的防腐剂、用于增强吸收和/或生物利用度的吸收促进剂,和/或其他增溶剂或分散剂,诸如本领域已知的那些。
用于肠胃外施用的示例性组合物包括可注射溶液或悬浮液,所述可注射溶液或悬浮液可含有例如合适的无毒的肠胃外可接受的稀释剂或溶剂,诸如甘露糖醇、1,3-丁二醇、水、林格氏溶液、等渗氯化钠溶液或其他合适的分散剂或润湿剂和悬浮剂,包括合成的甘油单酯或甘油二酯和脂肪酸(包括油酸)。
用于直肠施用的示例性组合物包括栓剂,所述栓剂可含有例如合适的无刺激性赋形剂,诸如可可脂、合成甘油酯或聚乙二醇,它们在常温下为固体但在直肠腔中液化和/或溶解以释放药物。
本发明的化合物的治疗有效量可以由本领域普通技术人员确定,并且包括对于哺乳动物的每天约0.05至1000mg/kg、1-1000mg/kg、1-50mg/kg、5-250mg/kg、250-1000mg/kg体重的活性化合物的示例性剂量,其可以单剂量或以单独的分剂量的形式(诸如每天1至4次)施用。应理解,任何特定受试者的特定剂量水平和剂量频率可以变化,并且将取决于多种因素,包括所用的特定化合物的活性,该化合物的代谢稳定性和作用时间长度,受试者的物种、年龄、体重、总体健康、性别和饮食,施用的模式和时间,排泄速率,药物组合,以及特定病症的严重性。用于治疗的优选受试者包括动物,最优选哺乳动物物种,诸如人;以及家畜,诸如狗、猫、马等。因此,当本文使用术语“患者”时,所述术语旨在包括通过调节IL-23、IL-12和/或IFNa介导的功能而受影响的所有受试者,最优选哺乳动物物种。
制备方法
本发明的化合物可通过有机化学领域技术人员可用的多种方法合成。下面描述了用于制备本发明化合物的通用合成方案。这些方案是说明性的,并且不意在限制本领域技术人员可用于制备本文公开化合物的可能技术。制备本发明化合物的不同方法对于本领域技术人员而言是清楚的。另外,合成中的各个步骤可以以交替的顺序进行,以便得到所希望的一种或多种化合物。通过通用方案中描述的方法制备的本发明化合物的例子在下文列出的制备和实施例章节中给出。
实施例
式(I)的化合物和用于制备式(I)的化合物的中间体的制备可以使用以下实施例中示出的程序和有关程序来制备。这些实施例中使用的方法和条件,以及在这些实施例中制备的实际化合物并不意在限制,而意在显示可以如何制备式(I)的化合物。当不通过本文所述的方法程序时,这些实施例中使用的起始材料和试剂通常是可商购的,或者报道在化学文献中,或者可以通过使用化学文献中所述的程序制备。
在给出的实施例中,短语“进行干燥和浓缩”通常是指将在有机溶剂中的溶液经硫酸钠或硫酸镁干燥,接着过滤并且从滤液中除去溶剂(通常在减压下并且在适用于所制备的材料的稳定性的温度下)。使用Isco中压色谱装置(Teledyne Corporation)用预填充的硅胶柱进行柱色谱法,用所指示的溶剂或溶剂混合物洗脱。使用ChemDraw Ultra,版本9.0.5(CambridgeSoft)确定化学名称。可以使用以下缩写:
缩写
化合物的分析纯度通过使用以下方法测定:
分析型HPLC方法A:SUNFIRE C18[150x4.6 mm]柱;pH 2.5的在水中的0.05%三氟乙酸作为缓冲液;流动相A=缓冲液:MeCN[95:5];流动相B:MeCN:缓冲液[95:5];10%B至100%B;23min;流速:1.0mL/min);
分析型HPLC方法B:XBridge Phenyl C18[150x4.6 mm]柱;pH 2.5的在水中的0.05%三氟乙酸作为缓冲液;流动相A=缓冲液:MeCN[95:5];流动相B:MeCN:缓冲液[95:5];10%B至100%B;23min;流速:1.0mL/min);
分析型LCMS方法C:BEH C18[2.1x50 mm,1.7μm颗粒]柱;0.05%三氟乙酸作为缓冲液;流动相A=水;流动相B:MeCN;2%B至98%B(0至1min);98%B(1min至1.5min);98%-2%B(1.5min至1.6min)。梯度时间(总)=1.6min。分析时间=2.2min。流速:0.8mL/min。检测器:在254nM处的UV和MS(ESI+)
实施例1
步骤1:
将6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-N-甲基烟酰胺(11g,25.9mmol)和碳酸钾(10.72g,78mmol)合并在具有260mL乙腈(商业级无水的)的500mL烧瓶中。将浆料在室温下搅拌30分钟,并且然后添加碘化钠(11.63g,78mmol)和二叔丁基(氯甲基)磷酸酯(在MeCN中的27.3wt%,密度=0.824g/mL,89mL,78mmol)。容器配备有水冷却冷凝器并且加热至50℃持续18小时。将反应冷却至室温并且通过硅藻土过滤,用约800mL DCM:MeOH(1:1)洗脱。将滤液浓缩并且继续。双烷基化(主要):LC保留时间0.92[C]。MS(E+)m/z:870.7(MH+)。单烷基化(区域异构体未知):LC保留时间0.82[C]。MS(E+)m/z:648.5(MH+)。
步骤2:
将步骤1的粗制产物溶解在乙酸(28.8mL)和水(14mL)中,溶液最初是均质的,但在产物形成时变成浆料。一旦完成转化成所希望的材料,就添加水(-200mL)。将浆料进行超声处理并且然后在室温下搅拌。将器皿在冰箱中短暂冷却直到溶液低于室温,此时将沉淀物滤出并且用水(15mL)冲洗。将滤饼风干并且然后用乙醚(1L)洗涤。收集固体,在DCM(20mL)中超声处理,并且然后过滤,收集所得固体(4.6g)。LC保留时间0.59[C]。MS(E+)m/z:536.1(MH+)。
步骤3:
将游离酸(6.75g,通过HPLC,-90%纯)悬浮在MeCN(25mL)和DDI水(90mL)中。经-1min向其中添加1M NaOH(水溶液,27.7mL,27.7mmol)。浓稠的棕色悬浮液变成细乳白色悬浮液。搅拌5分钟后,将溶液通过两个中级玻璃料过滤,提供略微浑浊的黄色溶液。添加水(200mL)以产生几乎均匀的溶液。向其中添加丙酮,直到总体积为约3L,此时添加籽晶并且立即形成细白色晶体,其量迅速增加。15分钟后,细悬浮液占优。另外30分钟后,添加另外的丙酮(总体积=4L)并且将悬浮液在8℃下储存过夜。通过过滤收集固体,用丙酮冲洗。收集固体,并且然后在约200mL丙酮中研磨和超声处理。通过过滤收集产物,并且在真空(<0.1托)下干燥过夜以提供4.75g小黄色晶体(72%产率,8.12mmol)。13C NMR(126MHz,氧化氘)δ182.7,167.6,161.7,156.4,153.4,150.4,140.5,133.5,126.3,125.8,125.3,120.8,109.3,99.4,74.4,74.4,61.2,39.6,17.2,7.7.1H NMR(500MHz,氧化氘)δ8.43(s,1H),7.58(dd,J=1.22,7.78Hz,1H),7.43(dd,J=1.22,7.93Hz,1H),7.25(t,J=7.93Hz,1H),6.95(s,1H),5.60(d,J=9.16Hz,2H),4.38(s,3H),3.56(s,3H),1.60-1.72(m,1H),0.66-0.81(m,4H)
LC保留时间0.59[C]。MS(E+)m/z:536.1(MH+)。
实施例2
步骤1
向6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(0.5g,1.175mmol)在DMF(9.04mL)中的悬浮液中以单一批次添加碳酸铯(11.49g,35.3mmol)并且将所得混合物在室温下搅拌30分钟。然后将二叔丁基(氯甲基)磷酸酯(1.288mL,5.88mmol)添加到反应中并且将反应混合物在室温下搅拌15小时。15小时后,反应不完全,因此添加另外的二叔丁基(氯甲基)磷酸酯(1.288ml,5.88mmol),并且继续反应另外24小时。将水添加到反应混合物中,并且将产物用乙酸乙酯(x2)萃取,将合并的有机层用水和盐水洗涤,并且然后经无水硫酸钠干燥,过滤并且浓缩。粗制产物如回收那样继续。LC保留时间0.77[C]。MS(E+)m/z:648.5(MH+)。
步骤2
将来自步骤1的粗制混合物溶解在丙酮(4mL)和水(4mL)中,并且将溶液加热至50℃,直到反应完成(1小时)。将反应使用旋转蒸发器和室温加热浴在减压下浓缩。将粗制产物用水(总体积=60mL)稀释,并且然后用DCM(约500mL x2)洗涤。将水层直接加载到反相(gold)isco 50g柱筒上,并且使用水(DDI,无缓冲液)/MeCN(无缓冲液)梯度(0-40%MeCN:H2O)进行纯化。1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),9.38(br.s.,1H),8.58(s,1H),8.21(s,1H),7.83(d,J=7.9Hz,1H),7.56(d,J=6.7Hz,1H),7.36(t,J=7.9Hz,1H),5.91(d,J=11.7Hz,2H),3.95(s,3H),3.76(s,3H),2.32(d,J=1.8Hz,1H),1.06-0.76(m,4H).LC保留时间0.54[C]。MS(E+)m/z:536.4(MH+)。部分地通过与实施例1的类比,也通过由在氢氧化钠中的长期暴露而产生的分解产物的小分子晶体结构来确定结构:
二叔丁基(氯甲基)磷酸酯
制备磷酸二叔丁酯钾盐(8.5g,34.2mmol)、碳酸氢钠(11.50g,137mmol)和四丁基硫酸氢铵(1.162g,3.42mmol)在DCM(104mL)和水(124mL)中的溶液并且在0℃下搅拌15分钟。向其中添加氯磺酸氯甲酯(6.93mL,68.5mmol)并且使反应混合物达到室温,搅拌过夜。将反应混合物用DCM(100ml)稀释并且用水(4x 200mL)洗涤并且然后用盐水洗涤。将有机层经无水硫酸钠干燥,过滤并且在真空中在不加热的情况下浓缩(温度维持低于25℃)以得到无色液体。
1H NMR(500MHz,氯仿-d)δ5.58(d,J=14.8Hz,2H),1.46(d,J=0.8Hz,18H)。
实施例3
步骤1
(E)-6-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-N-甲基-1-((甲硫基)甲基)-1,6-二氢吡啶-3-甲酰胺
向6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-N-甲基烟酰胺(0.500g,1.184mmol)在DMF(10mL)中的溶液中添加碳酸钾(0.981g,7.10mmol)。将混合物在室温下搅拌30min并且然后添加氯甲基甲基硫醚(0.977mL,11.84mmol)和碘化钠(0.887g,5.92mmol)。将混合物在50℃下在氮气下搅拌16h。将反应混合物用水稀释并且用乙酸乙酯(3x 50mL)萃取。将有机层经无水硫酸钠干燥并且在真空中浓缩。将残余物通过RP-HPLC纯化(制备柱:kinetex C18(150x 21.2mm;5微米),流动相A:4.5pH的10mM乙酸铵,流动相B:乙腈,流速:18mL/min,梯度:0/20、30/100)得到呈浅黄色固体的标题化合物(0.230g,0.477mmol,40.3%产率)。1H NMR(400MHz,DMSO-d6)δ0.64-0.76(m,4H),1.45-1.56(m,1H),2.26(s,3H),2.82(d,J=4.02Hz,3H),3.74(s,3H),4.46(s,3H),5.21(s,2H),7.36(br.s,1H),7.66(br.s,2H),8.00(br.s,1H),8.50(s,1H),8.55-8.69(br.s,1H);LC-MS(ES):m/z=483.2[M+H]+
步骤2
(E)-1-(氯甲基)-6-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-N-甲基-1,6-二氢吡啶-3-甲酰胺
向在0℃下的(E)-6-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-N-甲基-1-((甲硫基)甲基)-1,6-二氢吡啶-3-甲酰胺(0.100g,0.207mmol)在二氯甲烷(2.5mL)中的溶液中添加硫酰氯(0.084mL,1.036mmol)。将混合物在0℃下搅拌30min并且在真空中在30℃下浓缩以得到呈灰白色固体的标题化合物(0.110g,0.198mmol,95%产率)。粗制产物按原样使用。LC-MS(ES):m/z=471.2[M+H]+
步骤3
(E)-3-(2-((双(苄氧基)磷酰基)氧基)-4,6-二甲基苯基)-3-甲基丁酸(2-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-5-(甲基氨基甲酰基)吡啶-1(2H)-基)甲酯
向在0℃下的(E)-1-(氯甲基)-6-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-N-甲基-1,6-二氢吡啶-3-甲酰胺(0.110g,0.234mmol)和DIPEA(0.245mL,1.402mmol)在四氢呋喃(2mL)中的溶液中添加3-(2-((双(苄氧基)磷酰基)氧基)-4,6-二甲基苯基)-3-甲基丁酸(0.169g,0.350mmol)。将混合物在室温下搅拌3h并且然后在30℃下在真空中浓缩以得到呈棕色胶状物的粗制产物。RP-HPLC纯化(制备柱:X-bridge phenyl(250x 19mm;5微米),流动相A:4.5pH的在水中的10mM乙酸铵,流动相B:乙腈,流速:18mL/min,梯度:0/30、15/80)得到呈灰白色固体的标题化合物(0.115g,0.119mmol,50.8%产率)。1H NMR(300MHz,DMSO-d6)δ0.55-0.69(m,4H),1.49(s,7H),2.01-2.08(s,3H),2.39(s,3H),2.77(d,J=4.15Hz,3H),2.91(s,2H),3.72(s,3H),4.46(s,3H),5.11(d,J=8.31Hz,4H),5.88(br.s,2H),6.64(s,1H),6.88(s,1H),7.23-7.40(m,10H),7.51-7.60(m,1H),7.66(br.s,1H),7.90(br.s,1H),8.30(s,1H),8.49-8.58(m,1H),10.79(s,1H);LC-MS(ES):m/z=917.4[M+H]+
步骤4
(E)-3-(2,4-二甲基-6-(膦酰氧基)苯基)-3-甲基丁酸(2-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-5-(甲基氨基甲酰基)吡啶-1(2H)-基)甲酯
向在0℃下的(E)-3-(2-((双(苄氧基)磷酰基)氧基)-4,6-二甲基苯基)-3-甲基丁酸(2-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-5-(甲基氨基甲酰基)吡啶-1(2H)-基)甲酯(0.090g,0.098mmol)在1,2-二氯乙烷(4mL)中的溶液中添加TFA(0.756mL,9.82mmol)和茴香醚(0.536mL,4.91mmol)。在50℃下搅拌1h后,在真空下除去溶剂以得到粗制产物。RP HPLC纯化(制备柱:Sunfire C18(150x 19mm;5微米),流动相A:在水中的10mM乙酸铵,流动相B:乙腈,流速:18mL/min,梯度:0/10、25/100)后,获得呈灰白色固体的标题化合物(0.015g,0.020mmol,20.52%产率)。1H NMR(400MHz,DMSO-d6)δ0.73-0.97(m,4H),1.31-1.67(m,6H),1.83-1.95(m,3H),2.09-2.29(m,4H),2.73-3.00(m,3H),3.09-3.21(m,2H),3.72-3.83(m,3H),4.35-4.54(m,3H),5.79-5.96(m,2H),6.17-6.27(m,1H),6.97-7.06(m,1H),7.43-7.52(m,2H),7.59-7.70(m,1H),7.81-7.92(m,1H),8.71-8.79(m,1H).LC-MS(ES):m/z=737.2[M+H]+;HPLC保留时间和纯度:6.410min和98.91%(方法A)以及7.749min和98.89%(方法B)。
实施例4
步骤-1
€-6-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-N-(甲基-d3)-1-((甲硫基)甲基)-1,6-二氢吡啶-3-甲酰胺
向6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-N-(甲基-d3)烟酰胺(0.500g,1.175mmol)和碳酸钾(0.975g,7.05mmol)在DMF(10mL)中的混合物中添加氯甲基甲基硫醚(0.970mL,11.75mmol)和碘化钠(0.881g,5.88mmol)。在氮气下在50℃下搅拌16h后,将反应混合物用水稀释并且用乙酸乙酯(3x 50mL)萃取。将有机层经无水硫酸钠干燥并且在真空中浓缩以得到粗制产物。粗制产物的RP-HPLC纯化(制备柱:Sunfire C18(150x 4.6mm;5微米),流动相A:10mM乙酸铵,流动相B:乙腈,流速:1.0mL/分钟,梯度:0/10、20/100)得到呈浅黄色固体的标题化合物(0.210g,0.424mmol,36.1%产率)。1H NMR(300MHz,DMSO-d6)δ0.58-0.79(m,4H),1.52-1.58(m,1H),2.07(s,3H),3.74(s,3H),4.46(s,3H),5.21(s,2H),7.35(t,J=7.80Hz,1H),7.60(br.S,1H),7.66(d,J=7.93Hz,1H),7.90-8.04(br.S,1H),8.49(s,1H),8.56-8.65(br.S,1H),10.71(br.S,1H);LC-MS(ES):m/z=486.2[M+H]+
步骤2
€-1-(氯甲基)-6-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-N-(甲基-d3)-1,6-二氢吡啶-3-甲酰胺
向在0℃下的€-6-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-N-甲基-1-((甲硫基)甲基)-1,6-二氢吡啶-3-甲酰胺(0.100g,0.206mmol)在二氯甲烷(2.5mL)中的溶液中添加硫酰二氯(0.083mL,1.030mmol)。将混合物在0℃下搅拌30min。将反应混合物在真空中在30℃下浓缩以得到呈灰白色固体的标题化合物(0.112g,0.199mmol,96%产率)。粗制产物按原样用于下一步骤。LC-MS(ES):m/z=474.2[M+H]+步骤3
€-3-(2-((双(苄氧基)磷酰基)氧基)-4,6-二甲基苯基)-3-甲基丁酸(2-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-5-((甲基-d3)氨基甲酰基)吡啶-1(2H)-基)甲酯
向在0℃下的€-1-(氯甲基)-6-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-N-甲基-1,6-二氢吡啶-3-甲酰胺(0.112g,0.199mmol)和DIPEA(0.208mL,1.191mmol)在四氢呋喃(2mL)中的溶液中添加3-(2-((双(苄氧基)磷酰基)氧基)-4,6-二甲基苯基)-3-甲基丁酸(0.144g,0.298mmol)。在室温下搅拌3h后,将反应混合物在真空中在30℃下浓缩。通过RP-HPLC纯化将残余物纯化(制备柱:kinetex C18(150x4.6mm;5微米),流动相A:10mM乙酸铵,流动相B:乙腈,流速:1.0mL/min,梯度:0/30、20/100、25/100、28/30、33/30)以得到呈灰白色固体的标题化合物(0.060g,0.063mmol,31.5%产率)。1H NMR(300MHz,DMSO-d6)δ0.55-0.69(m,4H),1.49(s,7H),2.05(s,3H),2.39(s,3H),2.91(s,2H),3.73(s,3H),4.46(s,3H),5.09(s,2H),5.12(s,2H),5.89(br.S,2H),6.64(s,1H),6.87(s,1H),7.23-7.41(m,10H),7.57(d,J=6.00Hz,1H),7.68(d,J=7.20Hz,1H),7.91(br.S,1H),8.30(s,1H),8.50(br.S,1H),10.79(br.S,1H);LC-MS(ES):m/z=920.4[M+H]+
步骤4
€-3-(2,4-二甲基-6-(膦酰氧基)苯基)-3-甲基丁酸(2-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-5-((甲基-d3)氨基甲酰基)吡啶-1(2H)-基)甲酯
向在0℃下的€-3-(2-((双(苄氧基)磷酰基)氧基)-4,6-二甲基苯基)-3-甲基丁酸(2-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-5-((甲基-d3)氨基甲酰基)吡啶-1(2H)-基)甲酯(0.045g,0.049mmol)在1,2-二氯乙烷(2mL)中的溶液中添加TFA(0.377mL,4.89mmol)和茴香醚(0.267mL,2.446mmol)。将混合物在50℃下搅拌1h。将反应混合物在真空下浓缩以得到粗制产物。RP-HPLC纯化(制备柱:SunfireC18(150x 19mm;5微米),流动相A:在水中的0.1%HCOOH,流动相B:乙腈,流速:18mL/min,梯度:0/30、10/45)得到呈灰白色固体的标题化合物(0.014g,0.018mmol,37.5%产率)。1HNMR(400MHz,DMSO-d6)δ0.79-0.88(m,4H),1.50(s,6H),1.95(s,3H),2.12(br.S,1H),2.32(s,3H),3.16(br.S,2H),3.78(s,3H),4.48(s,3H),5.90(s,2H),6.30(s,1H),7.05(s,1H),7.48(d,J=8.03Hz,2H),7.66(d,J=8.03Hz,1H),7.86(d,J=6.53Hz,1H),8.80(s,1H),10.10(br.S,1H),11.67(br.S,1H);LC-MS(ES):m/z=740.4[M+H]+;HPLC保留时间和纯度:6.386min和97.03%(方法A)以及7.746min和97.45%(方法B)。
实施例5
步骤1
4-((双(苄氧基)磷酰基)氧基)-3-甲氧基苯甲酸甲酯
向4-羟基-3-甲氧基苯甲酸甲酯(3.000g,16.47mmol)在二氯甲烷(30mL)中的溶液中添加N,N-二异丙基氨基磷酸二苄酯(8.30mL,24.70mmol),然后添加1H-四唑(73.0mL,24.70mmol)(在乙腈中0.45M),并且将混合物在室温下搅拌8h。将反应在0℃下冷却。添加H2O2(5.05mL,165mmol)。在室温下搅拌2h后,将反应混合物浓缩以除去乙腈,并且将剩余的水层用水稀释并且用乙酸乙酯(3x 100mL)萃取。将合并的有机层用盐水洗涤,经无水硫酸钠干燥,过滤并且浓缩。将粗制材料通过ISCO纯化[硅胶60-120目,柱尺寸80g,在己烷中的乙酸乙酯作为洗脱剂]。产物洗脱到在己烷中的30%乙酸乙酯以得到呈无色油状物的标题化合物(8.200g,15.94mmol,97%产率)。1H NMR(400MHz,CDCl3)δ3.84(s,3H),3.91(s,3H),5.16(s,2H),5.18(s,2H),7.25(d,J=8.00Hz,1H),7.31-7.37(m,10H),7.57(d,J=9.20Hz,2H).;LC-MS(ES):m/z=443.2[M+H]+
步骤2
4-((双(苄氧基)磷酰基)氧基)-3-甲氧基苯甲酸
在0℃下向4-((双(苄氧基)磷酰基)氧基)-3-甲氧基苯甲酸甲酯(3.000g,5.83mmol)在四氢呋喃(30mL)和水(30mL)中的溶液中添加LiOH(0.279g,11.66mmol)。在0℃下搅拌1h后,将混合物用乙酸乙酯(2x 100mL)萃取。将水层用1.5N HCl溶液酸化(pH约1)并且用乙酸乙酯(3x 100mL)萃取。将有机层用盐水溶液洗涤,经无水Na2SO4干燥,并且在真空中浓缩以得到呈无色胶状物的标题化合物(1.700g,1.746mmol,29.9%产率)。粗制产物按原样使用。1H NMR(400MHz,DMSO-d6)δ3.80(s,3H),5.17(s,2H),5.20(s,2H),6.85(dd,J=2.40,6.40Hz,1H),7.40-7.52(m,10H),7.53(dd,J=2.00,8.40Hz,1H),7.59(s,1H),12.60(br.s,1H).LC-MS(ES):m/z=429.0[M+H]+
步骤3
(E)-4-((双(苄氧基)磷酰基)氧基)-3-甲氧基苯甲酸(2-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-5-((甲基-d3)氨基甲酰基)吡啶-1(2H)-基)甲酯
向在0℃下的(E)-1-(氯甲基)-6-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-N-(甲基-d3)-1,6-二氢吡啶-3-甲酰胺(0.100g,0.211mmol)和DIPEA(0.221mL,1.266mmol)在四氢呋喃(5mL)中的溶液中添加4-((双(苄氧基)磷酰基)氧基)-3-甲氧基苯甲酸(0.205g,0.211mmol)。将混合物在室温下搅拌3h。将反应混合物在真空中在30℃下浓缩以得到呈棕色胶状物的粗制产物。RP-HPLC纯化(制备柱:Sunfire C18(150x 19mm;5微米),流动相A:在水中的0.1%甲酸,流动相B:乙腈,流速:18mL/min,梯度:0/10、10/45)得到呈灰白色固体的标题化合物(0.040g,0.026mmol,12.26%产率)。LC-MS(ES):m/z=866.2[M+H]+
步骤4
(E)-3-甲氧基-4-(膦酰氧基)苯甲酸(2-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-5-((甲基-d3)氨基甲酰基)吡啶-1(2H)-基)甲酯
在0℃下向(E)-4-((双(苄氧基)磷酰基)氧基)-3-甲氧基苯甲酸(2-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-5-((甲基-d3)氨基甲酰基)吡啶-1(2H)-基)甲酯(0.070g,0.081mmol)在1,2-二氯乙烷(2mL)中的溶液中添加TFA(0.623mL,8.08mmol),然后添加茴香醚(0.442mL,4.04mmol)。将混合物在50℃下搅拌2h并且随后在真空下浓缩以得到呈棕色胶状物的粗制产物。RP-HPLC纯化(制备柱:Sunfire C18(150x 19mm;5微米),流动相A:在水中的0.1%甲酸,流动相B:乙腈,流速:18mL/min,梯度:0/10、10/35)得到呈灰白色固体的标题化合物(0.026g,0.038mmol,46.4%产率)。1H NMR(400MHz,DMSO-d6)δ0.66-0.81(m,4H),1.71(br.s,1H),3.74(s,3H),3.81(s,3H),4.46(s,3H),6.27(br.s,2H),7.38(t,J=7.60Hz,1H),7.48-7.56(m,3H),7.61-7.68(m,1H),7.71-7.86(m,2H),8.74-8.93(m,2H),11.01-11.03(m,1H);LC-MS(ES):m/z=686.2[M+H]+;HPLC保留时间和纯度:10.082min和99.31%(方法A)以及11.877min和98.83%(方法B)。
实施例6
(E)-1-羟基环丙烷-1-甲酸(2-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-5-((甲基-d3)氨基甲酰基)吡啶-1(2H)-基)甲酯
向在0℃下的(E)-1-(氯甲基)-6-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-N-(甲基-d3)-1,6-二氢吡啶-3-甲酰胺(0.025g,0.032mmol)和DIPEA(0.033mL,0.190mmol)在四氢呋喃(2mL)中的溶液中添加1-羟基环丙烷甲酸(3.88mg,0.038mmol)。在室温下搅拌3h后,将反应混合物在真空中在30℃下浓缩以得到粗制产物。RP-HPLC纯化(制备柱:Sunfire(150x 4.6mm;5微米),流动相A:在水中的0.1%甲酸,流动相B:乙腈,流速:1.0mL/min,梯度:0/10、20/100)得到呈灰白色固体的标题化合物(0.011g,0.019mmol,59.9%产率)。1H NMR(400MHz,DMSO-d6)δ0.86-0.94(m,4H),1.04-1.09(m,2H),1.19-1.24(m,2H),2.07(m,1H),3.74(s,3H),4.46(s,3H),6.19(br.s,2H),6.42(br.s,1H),7.41-7.50(m,1H),7.64(s,1H),7.90(br.s,1H),9.01(br.s,1H),9.09(br.s,1H),10.94(br.s,1H),11.51(br.s,1H);LC-MS(ES):m/z=540.2[M+H]+;HPLC保留时间和纯度:10.047min和93.15%(方法A)并且12.826min和91.08%(方法B)。
实施例7
((6-(环丙烷甲酰胺基)-3-((甲基-d3)氨基甲酰基)哒嗪-4-基)(2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)甲基(2-(2-甲氧基乙氧基)乙基)磷酸氢酯
向磷酸二氢((6-(环丙烷甲酰胺基)-3-((甲基-d3)氨基甲酰基)哒嗪-4-基)(2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)甲酯(30mg,0.056mmol,1当量)在DMF(0.5mL)中的溶液中添加2-(2-甲氧基乙氧基)乙醇(8.08mg,0.067mmol,1.200当量)、EDC(10.74mg,0.056mmol)。将混合物在室温下搅拌16h。将粗制产物使用RP HPLC纯化(制备柱:Sunfire C18(19x 250mm;5微米),流动相A:在水中的10mM乙酸铵,流动相B:乙腈,流速:18mL/min,梯度:0/20、10/35)。将级分使用高真空在30℃下浓缩。将残余物溶解在乙腈和水的混合物中。将所得溶液冷冻并且冻干12h以得到呈淡黄色固体的标题化合物(15.6mg,0.024mmol,43.4%产率)。1H NMR(400MHz,D2O)δ8.43(s,1H),7.83(br.s,1H),7.68(d,J=8.03Hz,1H),7.49(dd,J=8.03,1.51Hz,1H),7.34(t,J=7.78Hz,1H),6.03(d,J=12.05Hz,2H),3.92-3.98(m,5H),3.55-3.63(m,7H),3.48-3.52(m,2H),3.29(s,3H),1.91(br.s,1H),0.98-1.02(m,4H).LC-MS(ES):m/z=638.2[M+H]+;HPLC保留时间和纯度:5.74min和99.51%(方法A)以及5.90min和99.44%(方法B)。
实施例8
(E)-新戊酸((((6-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-3-((甲基-d3)氨基甲酰基)哒嗪-1(6H)-基)甲氧基)(羟基)磷酰基)氧基)甲酯
向(E)-磷酸二氢(6-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(1-甲基-1H-1,2,4-三唑-3-基)苯基)氨基)-3-((甲基-d3)氨基甲酰基)哒嗪-1(6H)-基)甲酯(60mg,0.112mmol,3当量)在DMF(1mL)中的溶液中添加DIPEA(0.059mL,0.336mmol)和碘甲基新戊酸酯(81mg,0.336mmol)。将反应混合物在室温下搅拌16h。将反应混合物直接使用RP HPLC纯化(制备柱:Kinetex(21.2x 150mm;5微米),流动相A:0.1%甲酸,流动相B:乙腈,流速:20mL/min)。将级分使用高真空在30℃下浓缩。将残余物溶解在乙腈和水的混合物中,冷冻并且冻干12h以得到呈淡黄色固体的标题化合物(9.42mg,0.014mmol,12.37%产率)。1HNMR(400MHz,D2O)δ8.38(s,1H),7.77(s,1H),7.70(d,J=7.72Hz,1H),7.45(dd,J=7.97,1.51Hz,1H),7.33-7.38(m,1H),6.05(d,J=13.11Hz,2H),5.41(d,J=13.55Hz,2H),3.97(s,3H),3.51(s,3H),1.82(bs,1H),1.07(s,9H),0.93-1.01(m,4H).LC-MS(ES):m/z=650.2[M+H]+;HPLC保留时间和纯度:7.045min和95.58%(方法A)以及6.85min和95.71%(方法B)。
实施例9
步骤14,6-二氯-N-(甲基-d3)-N-((甲硫基)甲基)烟酰胺
向在0℃下的4,6-二氯-N-(甲基-d3)烟酰胺(450mg,2.163mmol)在无水DMF(10mL)中的搅拌溶液中添加NaH(112mg,2.81mmol)。将混合物搅拌1h。添加氯甲基甲基硫醚(230mg,2.379mmol)并且使反应混合物达到室温并且搅拌16h。将反应混合物用水(10mL)稀释并且乙酸乙酯(2x 50mL)萃取。将有机层用H2O(1x 10mL)和饱和NaCl(1x 10mL)洗涤,经无水Na2SO4干燥,过滤并且在减压下浓缩。将粗制产物使用CombiFlash纯化(40g硅胶柱;石油醚:乙酸乙酯,作为洗脱剂)。将所希望的产物使用在石油醚中的15%乙酸乙酯洗脱。将所希望的级分在减压下蒸发以提供呈棕色油状物的标题化合物(350mg,1.109mmol,46.2%产率)。1H NMR(300MHz,DMSO-d6)δ2.17(s,3H),4.37(s,1H),4.68(br.s 1H),7.96(d,J=10.80Hz,1H),8.48(d,J=6.90Hz,1H).LC-MS(ES):m/z=268.0[M+H]+
步骤26-氯-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-N-(甲基-d3)-N-((甲硫基)甲基)烟酰胺
在室温下向2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯胺(260mg,1.267mmol)和4,6-二氯-N-(甲基-d3)-N-((甲硫基)甲基)烟酰胺(340mg,1.267mmol)在无水THF(10mL)中的搅拌溶液中逐滴添加在THF中的1M LiHMDS(3.17mL,3.17mmol)。搅拌1h后,将反应混合物冷却至0℃,用饱和氯化铵溶液(50mL)淬灭,并且用乙酸乙酯(2x 50mL)萃取。将有机层用H2O(1x30mL)和饱和NaCl溶液(1x 30mL)洗涤。将有机层经无水Na2SO4干燥,过滤并且在减压下浓缩以提供呈棕色半固体的标题化合物(550mg,1.032mmol,81%产率)。LC-MS(ES):m/z=437.2[M+H]+
步骤36-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-N-(甲基-d3)-N-((甲硫基)甲基)烟酰胺
将在密封管中的6-氯-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-N-(甲基-d3)-N-((甲硫基)甲基)烟酰胺(550mg,1.259mmol)、环丙烷甲酰胺(118mg,1.385mmol)、Cs2CO3(1230mg,3.78mmol)、xantphos(146mg,0.252mmol)和Pd2(dba)3(115mg,0.126mmol)在无水二噁烷(10mL)中的搅拌悬浮液用氮气吹扫并且然后密封。将混合物在110℃下搅拌过夜。允许将反应混合物冷却至室温并且用乙酸乙酯(25mL)稀释。将黑色悬浮液通过硅藻土床过滤,并且将床用乙酸乙酯(50mL)洗涤。将滤液在减压下浓缩以提供呈黑色半固体的粗制产物。将残余物使用CombiFlash(40g硅胶柱;MeOH:氯仿,作为洗脱剂)纯化。将所希望的产物使用在氯仿中的4%MeOH洗脱。将所希望的级分在减压下蒸发以提供呈黄色固体的标题化合物(500mg,0.875mmol,69.5%产率)。1H NMR(400MHz,DMSO-d6)δ0.63-0.77(m,4H),1.97-1.99(m,1H),2.07(br.s,3H),3.70(s,3H),4.45(s,3H),4.67(s,2H),7.32(t,J=7.78Hz,1H),7.60-7.63(m,2H),8.00(s,1H),8.16(s,1H),8.48-8.51(m,1H),10.76(s,1H);LC-MS(ES):m/z=486.2[M+H]+
步骤4
磷酸二氢(6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-N-(甲基-d3)烟酰胺基)甲酯
向6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-N-(甲基-d3)-N-((甲硫基)甲基)
烟酰胺(100mg,0.206mmol)在无水THF(5mL)中的搅拌溶液中添加粉末状分子筛(15mg)和NIS(93mg,0.412mmol)。将反应混合物在室温下搅拌5min并且一次性添加磷酸(605mg,6.18mmol)。将反应混合物搅拌5min并且冷却至0℃。添加MeOH(1mL)并且然后通过添加饱和Na2CO3溶液将pH调节至大约8。将反应混合物通过硅藻土床过滤并且将床用THF(20mL)洗涤。将滤液在高真空下在30℃下浓缩以得到呈半固体的粗制产物。将粗制化合物在反相制备型HPLC中纯化(制备柱:INERTSIL ODS(250x 19mm;3.5微米),流动相A:水,流动相B:乙腈,流速:17mL/min,梯度:0/0、12/20)。将含有所希望的产物的制备级分在高真空下在30℃下浓缩。将残余物溶解在乙腈和水的混合物中并且将溶液冻干24h以提供呈灰白色固体的标题化合物(40mg,0.068mmol,33.1%产率)。1H NMR(400MHz,D2O)δ0.89-0.98(m,4H),1.83(m,1H),3.63-3.67(m,3H),4.45-4.49(m,3H),5.04-5.13(m,2H),7.36-7.46(m,1H),7.54-7.63(m,2H),7.71-7.81(m,1H),8.24-8.31(m,1H).LC-MS(ES):m/z=536.2[M+H]+;HPLC保留时间和纯度:5.918min和99.73%(方法A)以及5.748min和99.68%(方法B)。
实施例10
步骤1
N-(叔丁氧基羰基)-N-甲基甘氨酸(2-(甲基氨基)吡啶-3-基)甲酯
向(2-(甲基氨基)吡啶-3-基)甲醇(100mg,0.724mmol)在无水DCM(2mL)中的搅拌溶液中添加2-((叔丁氧基羰基)(甲基)
氨基)乙酸(137mg,0.724mmol)、EDC(180mg,0.941mmol)和最后DMAP(88mg,0.724mmol)。将反应混合物在室温下搅拌16h并且然后用水稀释并且用DCM萃取。将有机层用H2O和饱和NaCl洗涤,经无水Na2SO4干燥,过滤并且在减压下浓缩。将残余物使用CombiFlash纯化(12g硅胶柱;在石油醚中的40%乙酸乙酯)以提供呈棕色半固体的标题化合物(210mg,0.563mmol,78%产率)。1H NMR(400MHz,DMSO-d6)δ1.16-1.40(m,9H),2.82-2.87(m,6H),4.00(m,2H),4.99(d,J=14.56Hz,2H),6.18(br.s,1H),6.51(dd,J=7.03,5.02Hz,1H),7.37-7.43(m,1H),8.03(dd,J=5.02,1.51Hz,1H);LC-MS(ES):m/z=310.2[M+H]+
步骤2
N-(叔丁氧基羰基)-N-甲基甘氨酸(2-(((氯甲氧基)羰基)(甲基)氨基)吡啶-3-基)甲酯
向在0℃下的2-((叔丁氧基羰基)(甲基)氨基)乙酸(2-(甲基氨基)吡啶-3-基)甲酯(220mg,0.711mmol)在无水DCM(3mL)中的搅拌溶液中添加DIPEA(0.621mL,3.56mmol),然后逐滴添加氯甲酸氯甲酯(275mg,2.133mmol)。允许将反应混合物温热至室温并且搅拌3h。将反应混合物冷却至0℃,用饱和碳酸氢钠溶液处理并且用DCM萃取。将有机层用H2O和饱和NaCl洗涤,经无水Na2SO4干燥,过滤并且在减压下浓缩。将残余物使用CombiFlash纯化(12g硅胶柱;在石油醚中的30%乙酸乙酯)以提供呈黄色半固体的标题化合物(200mg,0.428mmol,60.2%产率)。LC-MS(ES):m/z=402.2[M+H]+
步骤3
(E)-甲基甘氨酸(2-((((2-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-5-(甲基氨基甲酰基)吡啶-1(2H)-基)甲氧基)羰基)(甲基)氨基)吡啶-3-基)甲酯三氟乙酸乙酸盐
向6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-N-甲基烟酰胺(150mg,0.355mmol)在无水乙腈(2.5mL)中的搅拌溶液中添加K2CO3(147mg,1.065mmol)、2-((叔丁氧基羰基)(甲基)氨基)乙酸(2-(((氯甲氧基)羰基)(甲基)氨基)吡啶-3-基)甲酯(428mg,1.065mmol)并且随后添加碘化钠(186mg,1.243mmol)。将反应混合物加热至80℃并且在氮气下搅拌30h。将反应混合物用水稀释并且用乙酸乙酯萃取。将有机层用H2O和饱和NaCl洗涤,经无水Na2SO4干燥,过滤并且在减压下浓缩以提供呈棕色半固体的单烷基化产物和二烷基化产物的混合物的粗制化合物。在0℃下向在无水DCM(5mL)中的此粗制混合物(400mg,0.170mmol)中添加在二噁烷中的4M HCl(5mL,20.00mmol)。搅拌15min后,将反应混合物浓缩至干。将粗制化合物通过反相制备型HPLC纯化(制备柱:Symmetry C8(300x 19mm;7微米),流动相A:在水中的0.1%TFA,流动相B:乙腈,流速:18mL/min,梯度:0/10、5/20)。将制备级分在高真空下在30℃下浓缩。将残余物溶解在乙腈和水的混合物中并且将溶液冻干以提供呈灰白色固体的标题化合物(20mg,0.024mmol,13.94%产率)。1H NMR(400MHz,MeOH-d4)δ0.95-1.02(m,4H)1.92-2.02(m,1H)2.77(s,3H)2.99(s,3H)3.37-3.45(m,3H)3.84(s,3H)4.04-4.11(m,2H)4.49(s,3H)5.14-5.34(m,2H)6.09-6.38(m,2H)7.42-7.56(m,2H)7.65-7.80(m,2H)7.99-8.09(m,2H)8.45-8.57(m,1H)8.70-8.94(m,1H).LC-MS(ES):m/z=688.2[M+H]+;HPLC保留时间和纯度:8.827min和99.49%(方法A)以及11.610min和95.18%(方法B)。
实施例11
步骤14-(((双(苄氧基)磷酰基)氧基)甲基)苯甲酸甲酯
在室温下向4-(羟甲基)苯甲酸甲酯(2g,12.04mmol)和四唑(27.3g,24.07mmol)在乙腈中的搅拌溶液中添加氨基磷酸二苄基二异丙酯(4.16g,12.04mmol)。
搅拌16h后,将反应混合物冷却至0℃,并且逐滴添加H2O2(2.108mL,24.07mmol)。在0℃下搅拌20min后,将混合物用饱和碳酸氢钠溶液淬灭并且用EtOAc萃取。将有机层用H2O和饱和NaCl洗涤。将有机层经无水Na2SO4干燥,过滤并且在减压下浓缩。将残余物使用CombiFlash纯化(40g硅胶柱;在石油醚中的25%乙酸乙酯,作为洗脱剂)。将所希望的级分在减压下蒸发以提供呈棕色半固体的标题化合物(3.0g,5.63mmol,46.8%产率)。1H NMR(300MHz,CDCl3)δ3.92(s,3H),4.99-5.08(m,6H),7.29-7.38(m,10H),7.42(dd,J=5.70,7.50Hz,2H),7.45-8.05(m,2H)。
步骤24-(((双(苄氧基)磷酰基)氧基)甲基)苯甲酸
向在0℃下的4-(((双(苄氧基)磷酰基)氧基)甲基)苯甲酸甲酯(1g,2.345mmol)在THF(10mL)中的搅拌溶液中逐滴添加LiOH(0.112g,4.69mmol)在水(10mL)中的溶液。允许将反应混合物温热至室温并且搅拌16h。将混合物冷却至0℃并且用1.5N HCl溶液(20mL)处理并且用EtOAc萃取。将有机层用H2O和饱和NaCl洗涤,经无水Na2SO4干燥,过滤并且在减压下浓缩以提供呈棕色固体的标题化合物(600mg,0.757mmol,32.3%产率)。粗制产物按原样使用。1H NMR(400MHz,MeOH-d4)δ8.02(d,J=8.00Hz,2H),7.48(d,J=8.0Hz,2H),7.42-7.32(m,10H),5.10-5.04(m,4H),4.70(s,2H)。
步骤3
(E)-4-(((双(苄氧基)磷酰基)氧基)甲基)苯甲酸(2-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-5-(甲基氨基甲酰基)吡啶-1(2H)-基)甲酯
向在0℃下的(E)-1-(氯甲基)-6-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-N-甲基-1,6-二氢吡啶-3-甲酰胺(50mg,0.106mmol)在无水THF(2.5mL)中的搅拌溶液中添加DIPEA(0.037mL,0.212mmol),然后添加4-(((双(苄氧基)磷酰基)氧基)甲基)苯甲酸(43.8mg,0.106mmol)。
将反应混合物在0℃下搅拌2h。然后将混合物用水(5mL)稀释并且用乙酸乙酯(2x25mL)萃取。将有机层用H2O(1x 10mL)和饱和NaCl(1x 10mL)洗涤。将有机层经无水Na2SO4干燥,过滤并且在减压下浓缩。将粗制化合物在反相制备型HPLC中纯化(制备柱:SUNFIRE C18(150x 19mm;5微米),流动相A:在水中的10mM乙酸铵,流动相B:乙腈,流速:18mL/min,梯度:0/30、10/70)。将含有所希望的产物的制备级分在高真空下在30℃下浓缩。将残余物溶解在乙腈和水的混合物中并且冻干24h以提供呈灰白色固体的标题化合物(20mg,0.023mmol,21.80%产率)。1H NMR(400MHz,MeOH-d4)δ0.69-714(m,2H),0.91-093(m,2H),1.61-1.7(m,1H),2.94(s,3H),3.82(s,3H),4.45(s,3H),5.02(s,2H),5.05(s,2H),5.07(s,2H),6.32(s,2H),7.31-7.40(m,11H),7.40(d,J=9.04Hz,3H),7.70(d,J=7.53Hz,1H),7.79(s,2H),7.99(d,J=8.03Hz,2H),8.52(s,1H);LC-MS(ES):m/z=847.2[M+H]+
步骤4
(E)-4-((膦酰氧基)甲基)苯甲酸(2-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-5-(甲基氨基甲酰基)吡啶-1(2H)-基)甲酯
向(E)-(2-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-5-(甲基氨基甲酰基)吡啶-1(2H)-基)甲基4-(((双(苄氧基)磷酰基)氧基)甲基)苯甲酸酯(20mg,0.024mmol)在无水DCE(0.7mL)中的搅拌溶液中添加茴香醚(2.58μL,0.024mmol),然后添加TFA(1.820pL,0.024mmol)。将反应混合物加热至50℃并且搅拌16h。将混合物在高真空下浓缩至干。将粗制化合物在反相制备型HPLC中纯化(制备柱:Xbridgephenyl(250x 19mm;5微米),流动相A:在水中的0.1%甲酸,流动相B:乙腈,流速:18mL/min,梯度:0/20、6/30)。将含有所希望的产物的制备级分在高真空下在30℃下浓缩。将残余物溶解在乙腈和水的混合物中,将其冻干24h以提供呈灰白色固体的标题化合物(10mg,0.015mmol,62.2%产率)。1H NMR(400MHz,DMSO-d6)δ0.55-0.74(m,4H),1.45-1.51m,1H),2.82(d,J=4.52Hz,3H),3.75(br.s,3H),4.46(s,3H),4.96(d,J=7.53Hz,2H),6.26(br.s,2H),7.37(br.s,1H),7.54(d,J=8.53Hz,2H),7.64(br.s,1H),7.70(br.s,1H),7.92(br.s,1H),7.97(d,J=8.03Hz,2H),8.65(s,1H),8.73(br.s,1H),10.77(br.s,1H);LC-MS(ES):m/z=667.2[M+H]+;HPLC保留时间和纯度:4.675min和98.23%(方法A)以及6.088min和98.58%(方法B)。
实施例12
3-((双(苄氧基)磷酰基)氧基)-4-甲氧基苯甲酸
向在0℃下的3-羟基-4-甲氧基苯甲酸(300mg,1.784mmol)在无水乙腈(10mL)中的搅拌溶液中添加1H-四唑(91mg,2.68mmol),然后逐滴添加二苄基二异丙基氨基磷酸酯(678mg,1.963mmol)。添加后,使反应混合物达到室温并且搅拌16h。将混合物冷却至0℃,并且逐滴添加H2O2(0.312mL,3.57mmol)。搅拌20min后,将反应混合物用乙酸乙酯(2x 25mL)萃取。将有机层用H2O(1x 10mL)和饱和NaCl(1x 10mL)洗涤,经无水Na2SO4干燥,过滤并且在减压下浓缩。将粗制化合物在反相制备型HPLC中纯化。(制备柱:SUNFIRE C18(150x 19mm;5微米),流动相A:在水中的0.1%甲酸,流动相B:乙腈,流速:18mL/min,梯度:0/10、10/55)。将含有所希望的产物的制备级分在高真空下在30℃下浓缩以提供呈浅黄色油状物的标题化合物(350mg,0.809mmol,45.3%产率)。1H NMR(300MHz,DMSO-d6)δ3.85(s,3H),5.16(s,2H),5.19(s,2H),7.22(d,J=8.31Hz,1H),7.75-7.77(m,10H),7.80(d,J=8.69Hz,2H),12.88(br.s,1H);LC-MS(ES):m/z=429.0[M+H]+
步骤2
(E)-3-((双(苄氧基)磷酰基)氧基)-4-甲氧基苯甲酸(2-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-5-(甲基氨基甲酰基)吡啶-1(2H)-基)甲酯
向在0℃下的(E)-1-(氯甲基)-6-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-N-甲基-1,6-二氢吡啶-3-甲酰胺(30mg,0.064mmol)在无水THF(2.5mL)中的搅拌溶液中添加DIPEA(0.1mL,0.573mmol),然后添加3-((双(苄氧基)磷酰基)氧基)-4-甲氧基苯甲酸(30.0mg,0.070mmol)。将反应混合物在0℃下搅拌2h。将混合物用水(10mL)稀释并且用乙酸乙酯(2x 25mL)萃取。将有机层用H2O(1x 10mL)和饱和NaCl(1x10mL)洗涤。将有机层经无水Na2SO4干燥,过滤并且在减压下浓缩以提供呈棕色半固体的标题化合物(80mg,0.046mmol,72.8%产率)。粗制产物按原样用于下一反应。LC-MS(ES):m/z=863.5[M+H]+
步骤3
(E)-4-甲氧基-3-(膦酰氧基)苯甲酸(2-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-5-(甲基氨基甲酰基)吡啶-1(2H)-基)甲酯
在室温下向(E)-3-((双(苄氧基)磷酰基)氧基)-4-甲氧基苯甲酸(2-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-5-(甲基氨基甲酰基)吡啶-1(2H)-基)甲酯(80mg,0.046mmol)在无水DCE(2.5mL)中的搅拌溶液中添加茴香醚(0.1mL,0.915mmol)并且然后添加TFA(0.2mL,2.60mmol)。将反应混合物加热至50℃并且搅拌16h。将反应混合物在高真空下浓缩至干。将粗制化合物在反相制备型HPLC中纯化。(制备柱:Kinetex C18(150x 19mm;5微米),流动相A:在水中的0.1%甲酸,流动相B:乙腈,流速:18mL/min,梯度:0/10、10/35)。将含有所希望的产物的制备级分在高真空下在30℃下浓缩。将残余物溶解在乙腈和水的溶剂混合物中并且将溶液冻干24h以提供呈灰白色固体的标题化合物(10mg,0.014mmol,31.0%产率)。1H NMR(400MHz,DMSO-d6)δ0.80-0.82(m,4H),1.99-2.00(m,1H),2.83(d,J=4.52Hz,3H),3.75(s,3H),3.86(s,3H),4.46(s,3H),6.38(br.s,2H),7.03-7.45(m,4H),7.66-7.73(m,2H),7.84(br.s,1H),8.03(s.,1H),9.03-9.24(m,1H),11.35(br.s,1H);LC-MS(ES):m/z=683.2[M+H]+;HPLC保留时间和纯度:10.551min和98.75%(方法A)以及12.137min和98.30%(方法B)。
实施例13
步骤1
(E)-4-(((双(苄氧基)磷酰基)氧基)甲基)苯甲酸(2-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-5-((甲基-d3)氨基甲酰基)吡啶-1(2H)-基)甲酯
向在0℃下的(E)-1-(氯甲基)-6-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-N-(甲基-d3)-1,6-二氢吡啶-3-甲酰胺(80mg,0.169mmol)在无水THF(2.5mL)中的搅拌溶液中添加DIPEA(0.059mL,0.338mmol),然后添加4-(((双(苄氧基)磷酰基)氧基)甲基)苯甲酸(104mg,0.253mmol)。将反应混合物在0℃下搅拌2h。将混反应合物用水(10mL)稀释并且用乙酸乙酯(2x 25mL)萃取。将有机层用H2O(1x 10mL)和饱和NaCl(1x 10mL)洗涤,经无水Na2SO4干燥,过滤并且在减压下浓缩。将粗制化合物在反相制备型HPLC中纯化(制备柱:X-bridge phenyl(250x 19mm;5微米),流动相A:在水中的10mM乙酸铵,流动相B:乙腈,流速:18mL/min,梯度:0/30、10/67)。将含有所希望的产物的制备级分在高真空下在30℃下浓缩。将残余物溶解在乙腈和水的混合物中并且将溶液冻干24h以提供呈灰白色固体的标题化合物(30mg,0.034mmol,20.08%产率)。LC-MS(ES):m/z=850.4[M+H]+
步骤2
(E)-4-((膦酰氧基)甲基)苯甲酸(2-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-5-((甲基-d3)氨基甲酰基)吡啶-1(2H)-基)甲酯
在室温下向(E)-4-(((双(苄氧基)磷酰基)氧基)甲基)苯甲酸(2-((环丙烷羰基)亚氨基)-4-((2-甲氧基-3-(2-甲基-2H-四唑-5-基)苯基)氨基)-5-((甲基-d3)氨基甲酰基)吡啶-1(2H)-基)甲酯(30mg,0.035mmol)在无水DCE(2.5mL)中的搅拌溶液中添加茴香醚(0.1mL,0.915mmol)并且然后添加TFA(0.2mL,2.60mmol)。将反应混合物加热至50℃并且搅拌16h。将反应混合物在高真空下浓缩至干。使用甲酸作为缓冲液将粗制化合物在反相制备型HPLC中纯化。将含有所希望的产物的制备级分在高真空下在30℃下浓缩。将残余物溶解在乙腈和水的混合物中并且将溶液冻干24h以提供呈灰白色固体的标题化合物(10mg,0.015mmol,41.5%产率)。1H NMR(400MHz,DMSO-d6)δ0.62-0.82(m,4H),1.65-1.75(m,1H),3.75(s,3H),4.46(s,3H),4.98(d,J=7.53Hz,2H),6.33(br.s,2H),7.28(s,1H),7.41(d,J=8.03Hz,1H),7.55(d,J=8.03Hz,2H),7.77(br.s,2H),7.99(d,J=8.03Hz,2H),8.85(br.s,2H),11.05(br.s,1H);LC-MS(ES):m/z=670.2[M+H]+;HPLC保留时间和纯度:11.080min和98.35%(方法A)以及11.919min和98.66%(方法B)。
实施例14
表1
如上表1所示,将实施例1的化合物口服给药于大鼠以确定在施用后是否存在任何循环的前药。发现在治疗剂量(5和25mpk)下,没有看到前药的暴露。还显示在150mpk剂量下观察到少于0.05%的前药。因此,这显示前药在体内转化为母体药物。
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CN117362343A (zh) * | 2022-07-08 | 2024-01-09 | 爱科诺生物医药(香港)有限公司 | 具有选择性抑制tyk2/jak1活性的化合物,包含其的药物组合物,及其应用 |
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- 2020-07-14 KR KR1020227004691A patent/KR20220034853A/ko unknown
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US20230167082A1 (en) | 2023-06-01 |
WO2021011513A1 (en) | 2021-01-21 |
KR20220034853A (ko) | 2022-03-18 |
EP3999499A1 (en) | 2022-05-25 |
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